Abstract 1629: Integrated genomic and functional characterization of type I and II endometrial cancers reveals unexpected differences in novel candidate treatments
Authors: Deep S. Pandya, Sabina Swierczek, Jean-Noel Billaud, Sara Farisello, Magdalena Swierczek, Steven Sieber, Vaagn Andikyan, Linus Chuang, John A. Martignetti
Journal: Cancer Research (2022)

Abstract Introduction: Endometrial cancer (EndoCA), is the most common cancer of the female genital tract and is one of the few cancers in which incidence and death rates continue to rise. EndoCA is divided into Type I and II cancers: with type II cancers having poorer prognoses and accounting for a disproportionate number of EndoCA deaths. We sought to identify unique and potential therapeutic targets in type II EndoCA and then functionally validate these candidate targets using EndoCA patient-derived cell lines (PDCL). Methods: Ten EndoCA tumors, five each type I/II, were collected at surgery and PDLC (n=10) generated. Whole transcriptomic was performed on all samples including normal endometrium (n=7) as a control. Data analysis was performed using QIAGEN informatics tools (CLC Genomics, QCI-T and IPA). Cell viability assays (MTT) were performed using all 10 PDCL following drug dosing and all experiments were performed three times and in triplicate. Results: We analyzed differential gene expression profiles to explore molecular specificities between type I and II EndoCA using tumor samples and their paired PDCLs (passage 1 and 5). Our analysis revealed high degree of overlap between PDCL and their paired tumors and strong transcriptomic resemblance between type I and II tumors. Given the unexpected degree of similarities, we were intrigued to functionally interrogate representative shared canonical signaling pathways (Z&amp;gt;2.5) (activation of Sirtuin, RhoGDI and PTEN) and (inhibition of IL-8 and NF-kB) and potential drivers (Z&amp;gt;2.5) (including DNMT3B, NPAT, PDLIM2, FLCN, SIRT3, KRAS) between tumors and PDCL as potential therapeutic targets and interrogate their effectiveness between type I and II tumors. Based on drug availability, only three drug targets were identified: KDM1A, SIRT3, and PDLIM2 and, respectively, Seclidemstat, Resveratrol and Birabresib as potential inhibitors. To investigate the effect of these drugs, cell viability was determined. All predicted candidates resulted in tumor cell death; however, and while neither predicted nor suggested by our in-silico model, we observed a consistently higher in vitro anti-tumor activity of two of the drugs in type II versus type I derived PDCL. Specifically, Seclidemstat, had an ~6x increase while Birabresib an ~10x increase in achieving cell death. Conclusions: We identified three novel targets/drug inhibitors using combined transcriptomic profiling and functional characterization of type I and II EndoCA. Intriguingly, while selected based on shared profiles, two of these targets/drugs had markedly, and unexpectedly, greater effect in type II versus type I tumors. Interestingly, both of these drugs - Seclidemstat and Birabresib - are currently being tested in phase I clinical trials as novel epigenetic agents in solid tumors. Studies continue to explore the effectiveness of these agents in EndoCA. Citation Format: Deep S. Pandya, Sabina Swierczek, Jean-Noel Billaud, Sara Farisello, Magdalena Swierczek, Steven Sieber, Vaagn Andikyan, Linus Chuang, John A. Martignetti. Integrated genomic and functional characterization of type I and II endometrial cancers reveals unexpected differences in novel candidate treatments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1629.